Long-term excessive use of alcohol is capable of damaging nearly every organ and system in the body. The adverse effects of chronic alcohol consumption on the brain include not only psychiatric disorders but also severe alcohol-related neuroinflammation and brain damage. Work done by us and others has shown that chronic alcohol exposure causes intestinal oxidative stress, epithelial barrier disruption, enhancement of gut leakiness, and consequent systemic endotoxemia and inflammation. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiota (dysbiosis), and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Moreover, our earlier work has shown that chronic alcohol exposure increases the expression and activity of phosphodiesterase-4 (PDE4), decreases cellular cAMP, and primes monocytes/macrophages, leading to exaggerated expression of endotoxin-inducible inflammatory cytokines, such as TNFa. Additionally, alcohol exposure leads to a deficiency in brain docosahexanoeic acid (DHA) which likely contributes to the development/augmentation of cerebral inflammation and neurodegenerative pathologies. We hypothesize that alcohol-mediated enteric dysbiosis, systemic endotoxemia and elevated inflammatory responses induce/exacerbate alcohol-associated neuropathologies, via TLR4- and PDE4-mediated signaling, DHA deficiency, microglial activation, neuroinflammation and injury. The proposed study is an intramural-extramural collaborative effort that combines the relevant expertise to investigate the complex interactive mechanisms involving intestinal dysbiosis, systemic endotoxemia and inflammatory responses (UofL), and cerebral DHA deficiency in alcohol-induced neuropathologies (NIAAA). Moreover, a translational aspect will examine the therapeutic potential of specific mechanism-based strategies in mitigating alcohol-induced injury. The Specific aims of the application are: Aim 1: Determine alcohol mediated changes in the gut bacterial composition and intestinal permeability and correlate these changes to the development of peripheral endotoxemia and brain inflammation. Aim 2: Examine the role of PDE4 in alcohol-induced brain inflammatory signaling associated with DHA deficiency and injury. Aim 3: Evaluate the therapeutic efficacy of three intervention strategies targeting (i) enteric dysbiosis, (ii) PDE4 activity, and (iii) DHA deficiency in attenuating alcohol mediated brain inflammation and injury.